Worldwide, colorectal cancer is the third most common cause of death in cancer and approximately one million individuals are diagnosed each year. Despite optimal surgical treatment and modern adjuvant chemotherapy half of patients have recurrences and ultimately die within 5 years from diagnosis. The most important prognostic factors are presence of lymph node or distant metastases, being found in about 50% of all cases. Patients with locoregional lymph node metastases, Duke's C/stage III, have about 60% 5-year survival after surgery, and when distant metastases are present, the 5-year survival rate is less than 10%. The established, adjuvant treatment in stage III patients is 5-Fluorouracil (5-FU)-based chemotherapy, improving absolute 5-year survival by approximately 10%. There is no evidence for a statistically significant survival benefit for chemotherapy in Duke's B/Stage II patients. However, 20% of patients being classified as lymph node negative will suffer from recurrent disease. Some of these patients are likely to be understaged, since it is widely accepted that accurate staging of colon cancer is difficult and heavily dependent on the number of lymph nodes analyzed by the pathologist. The sentinel node, originally defined in penile carcinoma, is the first lymph node to receive lymphatic drainage from a tumour. Sentinel node detection and analysis has recently been applied in colon cancer, improving staging considerably.
The immune system often appears informed about tumours, as shown by an accumulation of immune cells at tumour sites, which correlates with improved prognosis. Immuno competent cells respond to “danger” signals, which can be provided of growing tumours as a consequence of the genotoxic stress of cell transformation and disruption of the surrounding microenvironment. Under ideal conditions, these signals will induce inflammation, activate innate effector cells with antitumour activity, and stimulate professional antigen-presenting cells (APCs), particularly dendritic cells (DCs), to engulf tumour-derived antigens and migrate to draining lymph nodes to trigger an adaptive response by T and B lymphocytes. Thus, the immune system is capable of recognizing and eliminating tumour cells but unfortunately tumours often interfere with the development and function of immune responses. However, recent advances in cellular and molecular immunology suggest strategies, which may prevent antitumour responses. Briefly, the presence of a tumour indicates that the developing cancer was able to avoid detection or to escape or to overwhelm the immune response. Progressing tumours often exhibit strategies that promote evasion from immune recognition. Examples are physical exclusion of immune cells from tumour sites, poor immunogenicity due to reduced expression of major histocompatibility complex (MHC) or costimulatory proteins, and disruption of natural killer (NK) and natural killer T (NKT) cell recognition. Further, some tumours prevent triggering of an inflammatory response by secreting proteins such as interleukin 10 (IL-10) or vascular endothelial growth factor (VEGF) that interfere with DC activation and differentiation, or by blocking the production of proinflammatory molecules by increasing expression of the STAT3 protein. Even if a response is induced, tumour cells may escape elimination by losing targeted antigens, rendering tumour-reactive T cells anergic, inducing regulatory T cells, or specifically deleting responding T cells. The tumour that finally develops reflects selection of poorly immunogenic and/or immune-resistant malignant cells.
In the adjuvant setting, tumour immunotherapy offers an appealing alternative to traditional cytostatics. One strategy has been to expand and activate NK cells in vitro with out specific antigen by culture with IL-2 followed by infusion of large numbers of these NK cells back into patients alone or with high doses of IL-2. This approach, or administration of high doses of IL-2 to expand and activate NK cells entirely in vivo, has yielded antitumour activity and remission in a subset of patients (Rosenberg S A et al., J Natl Cancer Inst 85, 622, 1993). However, life-threatening toxicity often develops, largely due to the release of tumour necrosis factor (TNF) from activated NK cells. Other attempts to stimulate the innate specific T cell immunity have been done by different types of vaccines. Promising results from animal studies entailed a study in which autologous tumour cells and an adjuvant immunomodulating agent, bacillus Calmette-Guérin (BCG) was given in combination several times to 98 patients with colorectal cancer in a prospectively randomized study. No statistically significant differences were detected in survival but maybe a small decrease in recurrence rate in stage II colon cancer patients. Further studies were done but no statistical clinical benefit in disease-free interval or survival could be seen, not even when combined with 5-FU and Leucovorin. Carcinoembryonic antigen (CEA) is expressed by colon cancers and trials have been done to create a monoclonal antibody against CEA. In a study with 23 patients with advanced colorectal cancer 13 true anti-CEA responses were generated, but without clinical responses. Vaccines based on CEA antibodies in combination with 5-FU or based on CEA proteins have been done, but without any clinical responses. The first results with the murine anti-17-1A monoclonal antibody in stage III colon cancer seemed very promising with a 5 year reduction of overall death rate by 30% and a decrease in recurrence rate by 27%, but later analysis of a large randomized study showed no effectiveness superior to standard adjuvant chemotherapy treatment.
Recently, two targeted therapies have been registered for the use in metastatic colorectal cancer. Cetuximab is a monoclonal antibody blocking the epidermal growth factor receptor-EGFR) and Bevacizumab is the first registered monoclonal antibody targeting angiogenesis. Studies, so far, have shown a limited but significant additive increase in survival of metastatic colorectal cancer using a successive combination of these drugs. When comparing 5-FU/LV+irinotecan with 5-FU/LV+irinotecan+bevacizumab (including post-progression chemotherapy in 55% of both groups), the overall survival was 15.6 months and 20.3 months, respectively. However, side effects were very common, with a proportion of patients having severe adverse effects of 85%. Patients treated with bevacizumab developed hypertension in 22% of cases, arterial thrombothic event (10%) and gastrointestinal perforation (1.5%). At least 50% of the patients had hypertension, thrombosis or minor bleedings.
Thus, it is obvious that there is still a need for an effective and at the same time safe treatment of colon cancer and metastases of colon cancer.